23-O-substituted 5-O-mycaminosyltylonide derivatives

Details 23-O-substituted 5-O-mycaminosyltylonide derivatives 23-O-substituted 5-O-mycaminosyltylonide derivatives

2002-04-19

2004-06-22

Krishnan, Ganapathy (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S007400, C514S028000, C514S029000

Reexamination Certificate

active

06753415

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to a novel class of 4′-substituted 16-membered macrolides, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
Macrolide antibiotics play a therapeutically important role, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and to the number and nature (neutral or basic) of the sugars. Macrolides are classified according to the size of the lactone ring (12, 14, 15 or 16 atoms). The macrolide antibiotic families (14-, 15- and 16-membered ring derivatives) exhibit a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin and josamycin.
The 16-membered ring macrolide antibiotics constitute an important clinically useful series of naturally occurring compounds within the macrolide class of antibiotics, as they show some advantages over 14-membered ring compounds (gastrointestinal tolerance and activity against strains expressing resistance of the inducible type). Sixteen membered macrolides usually contain an amino-disaccharide-4-O-(L-mycarosyl)-D-mycaminose and/or D-desosamine. One class has only neutral sugars. The sixteen membered macrolides can be classified into two major groups—the leucomycins and the tylosin series.
The tylosin series is divided into two groups—IIA and IIB—which differ at the C-6-side chain and the nature of the sugars on the chromophore. Tylosin consists of a substituted 16-membered ring lactone (tylonolide), an aminosugar (D-mycaminose) attached to C-5, two neutral sugars (D-mycinose attached at C-23 and L-mycarose attached at C-4′) and an acetaldehyde at C-6.
Considerable research efforts have been carried out on tylosin and its derivatives but not much success has been observed with this subclass. The search for macrolides active against MLS
B
-resistant strains (MLS
B
=Macrolides-Lincosamides-Type B Streptogramines) has become a major goal, in addition to improving the overall profile of the macrolides in terms of acid stability, tolerance and pharmacokinetics.
SUMMARY OF THE INVENTION
The present invention provides a novel class of 5-O-mycaminosyltylonide (OMT) analogs possessing increased antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives. In addition, the present invention provides a class of 5-O-mycaminosyltylonide analogs that are more acid stable and overcome bacterial resistance.
In one embodiment, the present invention provides compounds represented by Formula I, or a pharmaceutically acceptable salt, ester or prodrug thereof:
In Formula I
A is selected from the group consisting of:
(1) —CHO or a protected aldehyde;
(2) —CN;
(3) —CH═N—NR
6
R
7
, wherein R
6
and R
7
are each independently selected from the group consisting of:
(a) hydrogen;
(b) C
1
-C
6
-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
(c) C
2
-C
6
-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
(d) C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic; and
(e) R
6
and R
7
, taken together with the nitrogen atom to which they are connected, form a 3- to 7-membered ring which may optionally contain a hetero-function selected from the group consisting of: —O—, —NH—, —N(C
1
-C
6
-alkyl)-, —N(aryl)-, —N(heteroaryl)-, —S—, —S(O)—, and —S(O)
2
—;
(4) —CH═N—OR
6
, where R
6
is as previously defined;
(5) —CH
2
X, wherein X is selected from the group consisting of:
(a) hydroxy or protected hydroxy;
(b) halogen;
(c) —NR
6
R
7
, where R
6
and R
7
are as previously defined;
(d) —NR
6
C(O)—R
8
, where R
6
is as previously defined and R
8
is selected from the group consisting of:
i. hydrogen;
ii. C
1
-C
6
-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
iii. C
2
-C
6
-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
iv. C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;
v. aryl;
vi. substituted aryl;
vii. heterocyclic; and
viii. substituted heterocyclic;
(e) —NR
6
C(O)—NR
7
R
8
, where R
6
, R
7
, and R
8
are as previously defined;
(f) —NR
6
—NR
7
R
8
, where R
6
, R
7
and R
8
are as previously defined;
(g) —NR
6
—NR
7
C(O)—R
8
, where R
6
, R
7
and R
8
are as previously described;
(h) —S(O)
n
—R
9
, where R
9
is selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where n is 0, 1 or 2;
(i) —S(O)
n
—(C
1
-C
6
-alkyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where n is as previously defined;
(j) —S(O)
n
—(C
2
-C
6
-alkenyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where n is as previously defined;
(k) —S(O)
n
—(C
2
-C
6
-alkynyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where n is as previously defined; and
(l) —O—M—Y, where M is:
i. absent,
ii. —C(O)—,
iii. —C(O)N(R
6
)—, where R
6
is as previously defined,
iv. C
1
-C
6
-alkyl-N(R
6
)—, where R
6
is as previously defined,
v. C
2
-C
6
-alkenyl-N(R
6
)—, where R
6
is as previously defined, or
vi. C
2
-C
6
-alkynyl-N(R
6
)—, where R
6
is as previously defined,
and where Y is:
i. hydrogen,
ii. C
1
-C
6
-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, —OR
6
, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where R
6
is as previously defined,
iii. C
2
-C
6
-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, —OR
6
, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where R
6
is as previously defined,
iv. C
2
-C
6
-alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, —OR
6
, aryl, substituted aryl, heterocyclic, and substituted heterocyclic, where R
6
is as previously defined,
v. aryl,
vi. substituted aryl,
vii. heterocyclic, or
viii. substituted heterocyclic;
(6) heterocyclic or substituted heterocyclic;
R
1
and R
2
are each independently selected from the group consisting of:
(1) hydrogen;
(2) hydroxy;
(3) protected hydroxy;
(4) —OC(O)—C
1
-C
12
-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —OR
6
, and —NR
6
R
7
, where R
6
and R
7
are as previously defined;
(5) —OR
6
, where R
6
is as previously defined;
(6) halogen;
(7) —NR
6
R
7
, where R
6
and R
7
are as previously defined; and
(8) R
1
and R
2
taken together are=O;
R
3
is selected from the group consisting of:
(1) hydrogen;
(2) a hydroxy protecting group;
(3) —C(O)—C
1
-C
12
-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, het

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